Olanzapine Form I (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine) having endotherm at 179° C. (weak) and 195° C. (strong), Form I, is used for pharmaceutical formulations. It is known that commercially available Olanzapine Form I prepared by methods of the prior art, for example, as disclosed in U.S. Pat. No. 5,229,382, exhibits color which is less than desirable for commercial pharmaceutical use especially since the color is found to change over time due to the exposure in air
Investigators have disclosed, in U.S. Pat. No. 5,637,584, the solvated form of Olanzapine Form I as a mono (methylene chloride) solvate of Olanzapine. When the mono methylene solvate is crystallized from methylene chloride, Olanzapine Form I is generated.
Polymorphic Olanzapine Form I can also be prepared as a solvate of dimethylsulfoxide and water having different ratio (Olanzapine: DMSO:water) and then crystallization of this solvate form of crude Olanzapine using methylene chloride as a crystallization solvent to produce polymorphic form I of Olanzapine, as disclosed in WO 03/097650.
Others have disclosed a hydrate form of Olanzapine and the preparation of Olanzapine polymorph Form I from this hydrate and methods of converting Olanzapine form II to form I, as provided in WO 02/183390.
Recently preparation of Olanzapine Form I has focused on the generation of desired polymorphic Form I from the solvated Olanzapine using crystallization solvents.
Also, Olanzapine Form II is generated by prior art methods that include crystallization from ethyl acetate of the technical grade of Olanzapine Form I, as provided in U.S. Pat. No. 5,736,541.
The prior art, however, does not disclose a method for producing a stable Olanzapine Form I using rapid crystallization and seeding techniques to produce a novel polymorphic intermediate that is subjected to step-wise resulting in a pharmaceutically elegant and commercially useful amounts Olanzapine Form I having greater purity than that prepared by known methods.